Currently available electrophysiological approaches are limited in their ability to identify the majority of patients with CAD and LV dysfunction that succumb to sudden cardiac death (SCD). Over half of the patients developing SCD are not inducible at EP testing underscoring the need for new ways to identify substrates leading to arrhythmic death. Viable chronically dysfunctional or hibernating myocardium, not amenable to revascularization, appears to be a major risk factor for subsequent cardiac death and is present in up to 60 percent of patients with ischemic cardiomyopathy. Revascularization improves survival but most patients with hibernating myocardium are managed medically due to prohibitive procedural risks or technical limitations. Cause specific mortality data is limited but appears to be arrhythmic rather than from fatal MI or progressive CHF. In support of this, swine with hibernating myocardium develop SCD from VT/VF in the absence of MI or CHF. Potential triggers of lethal arrhythmias include regional reductions in SR calcium uptake and release proteins, myocyte hypertrophy and altered sympathetic innervation. The central hypothesis of this proposal is that the presence of hibernating myocardium as opposed to scar identifies a large subset of patients with ischemic cardiomyopathy that are at high risk for SCD. We further hypothesize that this risk is related to inhomogeneity in sympathetic innervation arising from chronic repetitive ischemia. We propose a prospective observational study that will enroll 360 patients with CAD, Class I-III CHF and an EF <= 35 percent. Using positron emission tomography (PET), the prevalence and amount ofhibemating myocardium will be quantified in patients that are not candidates for coronary revascularization. Aim 1 will determine whether imaging the mismatch between viability (preserved ( 18)F-2-deoxyglucose) and reduced resting flow (13)N-ammonia can predict an increased risk of SCD (or ICD discharge for VT/VF as a surrogate end-point) in hibernating myocardium. Aim 2 will image norepinephrine uptake using ( 11)C-hydroxyephedrine to determine whether inhomogeneity in myocardial sympathetic innervation predicts SCD risk better than viability testing. Aim 3 will identify whether the substrate identified by PET is stable after an aborted SCD event by evaluating temporal changes in function, viability and sympathetic innervation in patients with an ICD. Our long-term objective is to develop better approaches to identify patients with CAD who are most likely to benefit from primary prevention of SCD with placement of an ICD. [unreadable] [unreadable]